Background: The cardiovascular consequences of long-term exposure to low concentrations of mercury or arsenic are insufficiently understood. Mercury has been linked to cardiovascular risk in some, but not all, studies, and its association with the progression of atherosclerosis is uncertain. High arsenic exposure is an established cause of vascular disease, but the effect of low concentrations, more typical of the exposure of the US population, is essentially unknown. Since fish intake is the main source of methylmercury exposure in the general population, and a major source of organic arsenic compounds, the effects of these compounds may be confounded by the cardioprotective n-3 fatty acids in fish. Objective: To investigate the association of mercury and arsenic exposure with carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, in a cohort of individuals followed during 1989-99. Hypothesis: Exposure to mercury or arsenic, as determined in toenails, are associated with baseline carotid IMT and with its progression over 10 years follow-up. These associations are independent of established coronary risk factors and of plasma phospholipid long-chain n-3 fatty acids, a biomarker of fish oil intake. Setting: Cohort of 2,085 men and women, aged 45 years and older and residents in Washington County, MD, who participated simultaneously in the CLUE II cohort (that collected toenail clippings) and either in ARIC or in the CHS cohorts (that measured IMT and cardiovascular risk factors). Design and measurements: Prospective longitudinal study of the association of baseline mercury and arsenic levels with carotid IMT progression over 10 years. Toenail mercury and arsenic will be measured by instrumental neutron activation analysis, and plasma n-3 fatty acids by capillary gas chromatography. Carotid IMT has already been measured by B-mode ultrasound. Statistical analysis plan: Longitudinal data analysis methods will be used to model IMT progression. Important statistical issues will be the control of measurement error in repeated IMT measurements, the control of the effect of cardiovascular risk factors on IMT progression, and the evaluation of the joint effect of mercury or arsenic and n-3 fatty acids. Relevance: Confirmation of the role of mercury or arsenic on atherogenesis could impact current environmental and dietary public health recommendations. [unreadable] [unreadable]